Immune evasion strategies utilized by Francisella tularensis Public Deposited

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Last Modified
  • March 21, 2019
Creator
  • Barrigan, Lydia Marie
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Francisella tularensis is a highly pathogenic, gram-negative, facultative intracellular bacterium and the causative agent of tularemia. Francisella has evolved numerous mechanisms to evade host immune responses. One immune evasion mechanism utilized by Francisella is its ability to induce prostaglandin E2 (PGE2) secretion from infected host cells. We identified 20 Francisella genes necessary for the induction of PGE2 secretion in infected host cells. One of the genes necessary for PGE2 induction encodes a highly conserved AAA+ ATPase chaperone protein, ClpB. F. tularensis live vaccine strain (LVS) clpB is attenuated in vivo, despite normal intracellular growth in vitro. LVS clpB fails to inhibit pro-inflammatory cytokine responses in the lung early after inoculation, a process normally inhibited by LVS. The adaptive immune response is also altered compared to LVS with increased IFN-γ or IL-17A production by T cells. Although LVS clpB is attenuated, it induces an immune response that is as protective as LVS following lethal challenge indicating clpB is a potential target for vaccine development. Although the primary immune response is altered during LVS clpB infection, there are no differences in the secondary immune response to LVS. The primary immune response to LVS requires IFN-γ and IL-17A production to control bacterial replication. Few Th17 cells were identified during the secondary response in the lung whereas there were numerous CD4+ and CD8+ T cells producing IFN-γ. IFN-γ production is required for controlling bacterial replication during the secondary response, but IL-17A production is dispensable for survival during re-infection. Francisella also evades host immunity by targeting innate immune cells for infection. Francisella infects different cell types in the lung depending on the route of inoculation; alveolar macrophages are infected following intranasal inoculation while interstitial macrophages and neutrophils are infected in the lung after intradermal inoculation. The lung's cytokine milieu is more pro-inflammatory after intradermal inoculation compared to intranasal inoculation, consistent with the development of a more robust IFN-γ mediated adaptive immune response. A better understanding of the mechanisms of Francisella infection will not only result in understanding important concepts in pathogenesis, but will suggest key pathways to impact for the development of drugs and vaccines.
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  • In Copyright
Advisor
  • Frelinger, Jeffrey A.
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2013
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